Association analyses based on false discovery rate implicate new loci for coronary artery disease

Christopher P. Nelson; Anuj Goel; Adam S. Butterworth; Stavroula Kanoni; Tom R. Webb; Eirini Marouli; Lingyao Zeng; Ioanna Ntalla; Florence Y. Lai; Jemma C. Hopewell; Olga Giannakopoulou; Tao Jiang; Stephen E. Hamby; Emanuele Di Angelantonio; Themistocles L. Assimes; Erwin P. Bottinger; John C. Chambers; Robert Clarke; Colin N.A. Palmer; Richard M. Cubbon; Patrick Ellinor; Raili Ermel; Evangelos Evangelou; Paul W. Franks; Christopher Grace; Dongfeng Gu; Aroon D. Hingorani; Joanna M.M. Howson; Erik Ingelsson; Adnan Kastrati; Thorsten Kessler; Theodosios Kyriakou; Terho Lehtimäki; Xiangfeng Lu; Yingchang Lu; Winfried März; Ruth McPherson; Andres Metspalu; Mar Pujades-Rodriguez; Arno Ruusalepp; Eric E. Schadt; Amand F. Schmidt; Michael J. Sweeting; Pierre A. Zalloua; Kamal Alghalayini; Bernard D. Keavney; Jaspal S. Kooner; Ruth J.F. Loos; Riyaz S. Patel; Martin K. Rutter; Maciej Tomaszewski; Ioanna Tzoulaki; Eleftheria Zeggini; Jeanette Erdmann; George Dedoussis; Johan L.M. Björkegren; Heribert Schunkert; Martin Farrall; John Danesh; Nilesh J. Samani; Hugh Watkins; Panos Deloukas

doi:10.1038/ng.3913

Association analyses based on false discovery rate implicate new loci for coronary artery disease

Christopher P. Nelson, Anuj Goel, Adam S. Butterworth, Stavroula Kanoni, Tom R. Webb, Eirini Marouli, Lingyao Zeng, Ioanna Ntalla, Florence Y. Lai, Jemma C. Hopewell, Olga Giannakopoulou, Tao Jiang, Stephen E. Hamby, Emanuele Di Angelantonio, Themistocles L. Assimes, Erwin P. Bottinger, John C. Chambers, Robert Clarke, Colin N.A. Palmer, Richard M. CubbonPatrick Ellinor, Raili Ermel, Evangelos Evangelou, Paul W. Franks, Christopher Grace, Dongfeng Gu, Aroon D. Hingorani, Joanna M.M. Howson, Erik Ingelsson, Adnan Kastrati, Thorsten Kessler, Theodosios Kyriakou, Terho Lehtimäki, Xiangfeng Lu, Yingchang Lu, Winfried März, Ruth McPherson, Andres Metspalu, Mar Pujades-Rodriguez, Arno Ruusalepp, Eric E. Schadt, Amand F. Schmidt, Michael J. Sweeting, Pierre A. Zalloua, Kamal Alghalayini, Bernard D. Keavney, Jaspal S. Kooner, Ruth J.F. Loos, Riyaz S. Patel, Martin K. Rutter, Maciej Tomaszewski, Ioanna Tzoulaki, Eleftheria Zeggini, Jeanette Erdmann, George Dedoussis, Johan L.M. Björkegren, Heribert Schunkert, Martin Farrall, John Danesh, Nilesh J. Samani, Hugh Watkins, Panos Deloukas

College of Medicine and Health Sciences

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Abstract

Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

Original language	British English
Pages (from-to)	1385-1391
Number of pages	7
Journal	Nature Genetics
Volume	49
Issue number	9
DOIs	https://doi.org/10.1038/ng.3913
State	Published - 1 Sep 2017

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10.1038/ng.3913

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Nelson, C. P., Goel, A., Butterworth, A. S., Kanoni, S., Webb, T. R., Marouli, E., Zeng, L., Ntalla, I., Lai, F. Y., Hopewell, J. C., Giannakopoulou, O., Jiang, T., Hamby, S. E., Di Angelantonio, E., Assimes, T. L., Bottinger, E. P., Chambers, J. C., Clarke, R., Palmer, C. N. A., ... Deloukas, P. (2017). Association analyses based on false discovery rate implicate new loci for coronary artery disease. Nature Genetics, 49(9), 1385-1391. https://doi.org/10.1038/ng.3913

@article{74c1c0723169410185b092a0ad2a8194,

title = "Association analyses based on false discovery rate implicate new loci for coronary artery disease",

abstract = "Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.",

author = "Nelson, {Christopher P.} and Anuj Goel and Butterworth, {Adam S.} and Stavroula Kanoni and Webb, {Tom R.} and Eirini Marouli and Lingyao Zeng and Ioanna Ntalla and Lai, {Florence Y.} and Hopewell, {Jemma C.} and Olga Giannakopoulou and Tao Jiang and Hamby, {Stephen E.} and {Di Angelantonio}, Emanuele and Assimes, {Themistocles L.} and Bottinger, {Erwin P.} and Chambers, {John C.} and Robert Clarke and Palmer, {Colin N.A.} and Cubbon, {Richard M.} and Patrick Ellinor and Raili Ermel and Evangelos Evangelou and Franks, {Paul W.} and Christopher Grace and Dongfeng Gu and Hingorani, {Aroon D.} and Howson, {Joanna M.M.} and Erik Ingelsson and Adnan Kastrati and Thorsten Kessler and Theodosios Kyriakou and Terho Lehtim{\"a}ki and Xiangfeng Lu and Yingchang Lu and Winfried M{\"a}rz and Ruth McPherson and Andres Metspalu and Mar Pujades-Rodriguez and Arno Ruusalepp and Schadt, {Eric E.} and Schmidt, {Amand F.} and Sweeting, {Michael J.} and Zalloua, {Pierre A.} and Kamal Alghalayini and Keavney, {Bernard D.} and Kooner, {Jaspal S.} and Loos, {Ruth J.F.} and Patel, {Riyaz S.} and Rutter, {Martin K.} and Maciej Tomaszewski and Ioanna Tzoulaki and Eleftheria Zeggini and Jeanette Erdmann and George Dedoussis and Bj{\"o}rkegren, {Johan L.M.} and Heribert Schunkert and Martin Farrall and John Danesh and Samani, {Nilesh J.} and Hugh Watkins and Panos Deloukas",

note = "Funding Information: This work was funded by British Heart Foundation (BHF) grants RG/14/5/30893 to P.D. and FS/14/66/31293 to O.G. The work of P.D. forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre and Leicester Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). F.Y.L. and S.E.H. are funded by NIHR. C.P.N., T.R.W. and N.J.S. are funded from BHF, the Transatlantic Networks of Excellence Award (12CVD02) from the Leducq Foundation and EU-FP7/2007-2013 grant HEALTH-F2-2013-601456. N.J.S. is an NIHR Senior Investigator. PROCARDIS was supported by EU-FP6 (LSHM-CT-2007-037273), AstraZeneca, BHF, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar S{\"o}derberg Foundation, Karolinska Institutet, Foundation Strategic Research and the Stockholm County Council (560283). M.F. and H.W. are supported by Wellcome Trust award 090532/Z/09/Z, and M.F., H.W. and T.K. are supported by the BHF Centre of Research Excellence. A.G., H.W. and T.K. are supported by FP7/2007-2013 (HEALTH-F2-2013-601456 (CVGenes@Target)), and A.G. is supported by the Wellcome Trust and the TriPartite Immunometabolism Consortium-Novo Nordisk Foundation (NNF15CC0018486). HPS (ISRCTN48489393) was supported by the Medical Research Council (MRC), BHF, Merck and Co, and Roche Vitamins, Ltd. HPS acknowledges National Blood Service donor and UK-Twin Study controls (Wellcome Trust 07611, FP7/2007-2013). J.C.H. is funded by BHF (FS/14/55/30806). The Mount Sinai BioMe Biobank is supported by the Andrea and Charles Bronfman Philanthropies. The GLACIER Study and P.W.F. are funded by the European Commission (CoG-2015_681742_NASCENT), the Swedish Research Council (Distinguished Young Researchers Award), the Heart-Lung Foundation and the Novo Nordisk Foundation. OHGS studies were funded by the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Heart & Stroke Foundation of Canada. LURIC was funded from the EU-FP7 (Atheroremo (201668), RiskyCAD (305739), INTERREG IV Oberrhein Program), the European Regional Development Fund (ERDF), Wissenschaftsoffensive TMO and from the German Ministry for Education and Research, project e: AtheroSysMed (01ZX1313A-K). LOLIPOP is supported by the NIHR-BRC Imperial College Healthcare NHS Trust, BHF (SP/04/002), MRC (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), NIHR (RP-PG-0407-10371), EU-FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). The Helsinki Sudden Death Study was funded by EU-FP7 (201668, AtheroRemo), the Tampere University Foundation, Tampere University Hospital Medical Funds (grants 9M048 and 9N035 for T.L.), the Emil Aaltonen Foundation (T.L.), the Finnish Foundation of Cardiovascular Research (T.L., P.K.), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Yrj{\"o} Jahnsson Foundation, the Tampere Tuberculosis Foundation (T.L.), the Signe and Ane Gyllenberg Foundation (T.L.) and the Diabetes Research Foundation of the Finnish Diabetes Association (T.L.). Publisher Copyright: {\textcopyright} 2017 Nature America, Inc., part of Springer Nature. All rights reserved.",

year = "2017",

month = sep,

day = "1",

doi = "10.1038/ng.3913",

language = "British English",

volume = "49",

pages = "1385--1391",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "9",

}

Nelson, CP, Goel, A, Butterworth, AS, Kanoni, S, Webb, TR, Marouli, E, Zeng, L, Ntalla, I, Lai, FY, Hopewell, JC, Giannakopoulou, O, Jiang, T, Hamby, SE, Di Angelantonio, E, Assimes, TL, Bottinger, EP, Chambers, JC, Clarke, R, Palmer, CNA, Cubbon, RM, Ellinor, P, Ermel, R, Evangelou, E, Franks, PW, Grace, C, Gu, D, Hingorani, AD, Howson, JMM, Ingelsson, E, Kastrati, A, Kessler, T, Kyriakou, T, Lehtimäki, T, Lu, X, Lu, Y, März, W, McPherson, R, Metspalu, A, Pujades-Rodriguez, M, Ruusalepp, A, Schadt, EE, Schmidt, AF, Sweeting, MJ, Zalloua, PA, Alghalayini, K, Keavney, BD, Kooner, JS, Loos, RJF, Patel, RS, Rutter, MK, Tomaszewski, M, Tzoulaki, I, Zeggini, E, Erdmann, J, Dedoussis, G, Björkegren, JLM, Schunkert, H, Farrall, M, Danesh, J, Samani, NJ, Watkins, H & Deloukas, P 2017, 'Association analyses based on false discovery rate implicate new loci for coronary artery disease', Nature Genetics, vol. 49, no. 9, pp. 1385-1391. https://doi.org/10.1038/ng.3913

TY - JOUR

T1 - Association analyses based on false discovery rate implicate new loci for coronary artery disease

AU - Nelson, Christopher P.

AU - Goel, Anuj

AU - Butterworth, Adam S.

AU - Kanoni, Stavroula

AU - Webb, Tom R.

AU - Marouli, Eirini

AU - Zeng, Lingyao

AU - Ntalla, Ioanna

AU - Lai, Florence Y.

AU - Hopewell, Jemma C.

AU - Giannakopoulou, Olga

AU - Jiang, Tao

AU - Hamby, Stephen E.

AU - Di Angelantonio, Emanuele

AU - Assimes, Themistocles L.

AU - Bottinger, Erwin P.

AU - Chambers, John C.

AU - Clarke, Robert

AU - Palmer, Colin N.A.

AU - Cubbon, Richard M.

AU - Ellinor, Patrick

AU - Ermel, Raili

AU - Evangelou, Evangelos

AU - Franks, Paul W.

AU - Grace, Christopher

AU - Gu, Dongfeng

AU - Hingorani, Aroon D.

AU - Howson, Joanna M.M.

AU - Ingelsson, Erik

AU - Kastrati, Adnan

AU - Kessler, Thorsten

AU - Kyriakou, Theodosios

AU - Lehtimäki, Terho

AU - Lu, Xiangfeng

AU - Lu, Yingchang

AU - März, Winfried

AU - McPherson, Ruth

AU - Metspalu, Andres

AU - Pujades-Rodriguez, Mar

AU - Ruusalepp, Arno

AU - Schadt, Eric E.

AU - Schmidt, Amand F.

AU - Sweeting, Michael J.

AU - Zalloua, Pierre A.

AU - Alghalayini, Kamal

AU - Keavney, Bernard D.

AU - Kooner, Jaspal S.

AU - Loos, Ruth J.F.

AU - Patel, Riyaz S.

AU - Rutter, Martin K.

AU - Tomaszewski, Maciej

AU - Tzoulaki, Ioanna

AU - Zeggini, Eleftheria

AU - Erdmann, Jeanette

AU - Dedoussis, George

AU - Björkegren, Johan L.M.

AU - Schunkert, Heribert

AU - Farrall, Martin

AU - Danesh, John

AU - Samani, Nilesh J.

AU - Watkins, Hugh

AU - Deloukas, Panos

N1 - Funding Information: This work was funded by British Heart Foundation (BHF) grants RG/14/5/30893 to P.D. and FS/14/66/31293 to O.G. The work of P.D. forms part of the research themes contributing to the translational research portfolios of the Barts Biomedical Research Centre and Leicester Biomedical Research Centre funded by the UK National Institute for Health Research (NIHR). F.Y.L. and S.E.H. are funded by NIHR. C.P.N., T.R.W. and N.J.S. are funded from BHF, the Transatlantic Networks of Excellence Award (12CVD02) from the Leducq Foundation and EU-FP7/2007-2013 grant HEALTH-F2-2013-601456. N.J.S. is an NIHR Senior Investigator. PROCARDIS was supported by EU-FP6 (LSHM-CT-2007-037273), AstraZeneca, BHF, the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, Karolinska Institutet, Foundation Strategic Research and the Stockholm County Council (560283). M.F. and H.W. are supported by Wellcome Trust award 090532/Z/09/Z, and M.F., H.W. and T.K. are supported by the BHF Centre of Research Excellence. A.G., H.W. and T.K. are supported by FP7/2007-2013 (HEALTH-F2-2013-601456 (CVGenes@Target)), and A.G. is supported by the Wellcome Trust and the TriPartite Immunometabolism Consortium-Novo Nordisk Foundation (NNF15CC0018486). HPS (ISRCTN48489393) was supported by the Medical Research Council (MRC), BHF, Merck and Co, and Roche Vitamins, Ltd. HPS acknowledges National Blood Service donor and UK-Twin Study controls (Wellcome Trust 07611, FP7/2007-2013). J.C.H. is funded by BHF (FS/14/55/30806). The Mount Sinai BioMe Biobank is supported by the Andrea and Charles Bronfman Philanthropies. The GLACIER Study and P.W.F. are funded by the European Commission (CoG-2015_681742_NASCENT), the Swedish Research Council (Distinguished Young Researchers Award), the Heart-Lung Foundation and the Novo Nordisk Foundation. OHGS studies were funded by the Canadian Institutes of Health Research, the Canada Foundation for Innovation and the Heart & Stroke Foundation of Canada. LURIC was funded from the EU-FP7 (Atheroremo (201668), RiskyCAD (305739), INTERREG IV Oberrhein Program), the European Regional Development Fund (ERDF), Wissenschaftsoffensive TMO and from the German Ministry for Education and Research, project e: AtheroSysMed (01ZX1313A-K). LOLIPOP is supported by the NIHR-BRC Imperial College Healthcare NHS Trust, BHF (SP/04/002), MRC (G0601966, G0700931), the Wellcome Trust (084723/Z/08/Z), NIHR (RP-PG-0407-10371), EU-FP7 (EpiMigrant, 279143) and Action on Hearing Loss (G51). The Helsinki Sudden Death Study was funded by EU-FP7 (201668, AtheroRemo), the Tampere University Foundation, Tampere University Hospital Medical Funds (grants 9M048 and 9N035 for T.L.), the Emil Aaltonen Foundation (T.L.), the Finnish Foundation of Cardiovascular Research (T.L., P.K.), the Pirkanmaa Regional Fund of the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Tampere Tuberculosis Foundation (T.L.), the Signe and Ane Gyllenberg Foundation (T.L.) and the Diabetes Research Foundation of the Finnish Diabetes Association (T.L.). Publisher Copyright: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved.

PY - 2017/9/1

Y1 - 2017/9/1

N2 - Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

AB - Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10 '8) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; n cases = 10,801) as well as a stricter definition without angina (HARD; n cases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.

UR - http://www.scopus.com/inward/record.url?scp=85028693072&partnerID=8YFLogxK

U2 - 10.1038/ng.3913

DO - 10.1038/ng.3913

M3 - Article

C2 - 28714975

AN - SCOPUS:85028693072

SN - 1061-4036

VL - 49

SP - 1385

EP - 1391

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -

Association analyses based on false discovery rate implicate new loci for coronary artery disease

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